Actuators for microfluidics without moving parts

ABSTRACT

A series of microactuators for manipulating small quantities of liquids, and methods of using these for manipulating liquids, are disclosed. The microactuators are based on the phenomenon of electrowetting and contain no moving parts. The force acting on the liquid is a potential-dependent gradient of adhesion energy between the liquid and a solid insulating surface.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/430,816, filed May 6, 2003 (now U.S. Pat. No. 7,255,780), which is acontinuation of U.S. patent application Ser. No. 09/490,769, filed Jan.24, 2000 (now U.S. Pat. No. 6,565,727), which claims the benefit ofprovisional patent application No. 60/117,002, filed Jan. 25, 1999.

FIELD OF THE INVENTION

This invention relates generally to the fields of laboratory automation,microfabrication and manipulation of small volumes of fluids(microfluidics), in such a manner so as to enable rapid dispensing andmanipulation of small isolated volumes of fluids under direct electroniccontrol. More specifically, the invention relates to a method of formingand moving individual droplets of electrically conductive liquid, anddevices for carrying out this method.

BACKGROUND OF THE INVENTION

Miniaturization of assays in analytical biochemistry is a direct resultof the need to collect maximum data from a sample of a limited volume.This miniaturization, in turn, requires methods of rapid and automaticdispensing and manipulation of small volumes of liquids (solvents,reagents, samples etc.) The two methods currently employed for suchmanipulation are, 1) ink jetting and 2) electromigration methods incapillary channels: electroosmosis, elecrophoresis and/or combinationthereof. Both methods suffer poor reproducibility.

Ink jetting is based on dispensing droplets of liquid through a nozzle.Droplet expulsion from the nozzle is effected by a pressure pulse in thereservoir connected to the nozzle. The pressure pulse itself is effectedby an electric signal. The droplets are subsequently deposited on asolid surface opposing the nozzle. The relative position of the nozzleand the surface is controlled by a mechanical device, resulting indeposition of droplets in a desired pattern. Removal of the droplets istypically effected by either washing or spinning (centrifugal forces).

While ink jetting is a dispensing method generally applicable to a widevariety of liquids, the volume of the deposited droplets is not verystable. It depends on both the nature of the liquid being deposited(viscosity, density, vapor pressure, surface tension) and theenvironment in the gap between the surface and the nozzle (temperature,humidity). Ink jetting technology does not provide means to manipulatedroplets after they have been deposited on the surface, except forremoving them.

Electromigration methods are based on mobility of ions in liquids whenelectric current is passed through the liquids. Because different ionshave different mobilities in the electric field, the composition ofliquid being manipulated generally changes as it is being transported.While this feature of electromigration methods is, useful for analyticalpurposes, because it allows physical separation of components ofmixtures, it is undesirable in general micromanipulation techniques.

Additionally, the need to pass electrical current through the liquidresults in heating of the liquid, which may cause undesirable chemicalreactions or even boiling. To avoid this, the electrical conductivitiesof all liquids in the system are kept low, limiting the applicability ofelectromigration methods.

The need to pass electrical current through the liquid also requiresthat the control electrodes be electrically connected through anuninterrupted body of conductive liquid. This requirement additionallycomplicates precision dispensing and results in ineffective use ofreagents, because the metered doses of a liquid are isolated from acontinuous flow of that liquid from one electrode to another.

Additionally, ions present in the liquid alter the electric field inthat liquid. Therefore, changes in ionic composition in the liquid beingmanipulated result in variations in resultant distribution of flow andmaterial for the same sequence of control electrical signals.

Finally, the devices for carrying out the electromigration methods haveconnected channels (capillaries), which are used to define liquid flowpaths in the device. Because the sizes of these capillaries andconnections among them are optimized for certain types of manipulations,and also for certain types of liquids, these devices are veryspecialized.

SUMMARY OF THE INVENTION

The present invention provides microchip laboratory systems and methodsof using these systems so that complex chemical and biochemicalprocedures can be conducted on a microchip under electronic control. Themicrochip laboratory system comprises a material handling device thattransports liquid in the form of individual droplets positioned betweentwo substantially parallel, flat surfaces. Optional devices for formingthe droplets are also provided.

The formation and movement of droplets are precisely controlled byplurality of electric fields across the gap between the two surfaces.These fields are controlled by applying voltages to plurality ofelectrodes positioned on the opposite sides of the gap. The electrodesare substantially planar and positioned on the surfaces facing the gap.At least some of the electrodes are electrically insulated from theliquid in the gap.

The gap is filled with a filler fluid substantially immiscible with theliquids which are to be manipulated. The filler fluid is substantiallynon-conductive. The wetting properties of the surfaces facing inside thegap are controlled, by the choice of materials contacting the liquids orchemical modification of these materials, so that at least one of thesesurfaces is preferentially wettable by the filler fluid rather than anyof the liquids which are to be manipulated.

The operating principle of the devices is known as electrowetting. If adroplet of polar conductive liquid is placed on a hydrophobic surface,application of electric potential across the liquid-solid interfacereduces the contact angle, effectively converting the surface into morehydrophilic. According to the present invention, the electric fieldseffecting the hydrophobic-hydrophilic conversion are controlled byapplying an electrical potential to electrodes arranged as an array onat least one side of the gap. The electrodes on the other side may ormay not be arranged in a similar array; in the preferred embodiment,there is array of electrodes only on one side of the gap, while theother has only one large electrode covering substantially the entirearea of the device.

At least on one side of the gap, the electrodes are coated with aninsulator. The insulator material is chosen so that it is chemicallyresistant to the liquids to be manipulated in the device, as well as thefiller fluid.

By applying an electrical potential to an electrode or a group ofelectrodes adjacent to an area contacted by polar liquid, thehydrophobic surface on top of these electrodes is converted tohydrophilic and the polar liquid is pulled by the surface tensiongradient (Marangoni effect) so as to maximize the area overlap with thecharged group of electrodes.

By removing an electric potential from an electrode positioned betweenthe extremities of an elongated body of polar liquid, the portion offormerly hydrophilic surface corresponding to that electrode is madehydrophobic. The gradient of surface tension in this case acts toseparate the elongated body of liquid into two separate bodies, eachsurrounded by a phase boundary. Thus, individual droplets of polarliquid can be formed by alternatively applying and removing an electricpotential to electrodes. The droplets can be subsequently repositionedwithin the device as discussed above.

Examples of appropriate coating materials include SiN and BN, depositedby any of the conventional thin-film deposition methods (sputtering,evaporation, or preferably chemical vapor deposition) and parylene™,deposited by pyrolytic process, spin-on glasses (SOGs) and polymercoatings (polyimides, polymethylmetacrylates and their copolymers,etc.), dip- and spray-deposited polymer coatings, as well as polymerfilms (Teflon™, polyimides etc.) applied by lamination.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Cross-section of a planar electrowetting actuator according tothe invention

22—top wafer

24—bottom wafer

26—liquid droplet

28 a—bottom hydrophobic insulating coating

28 b—top hydrophobic insulating coating

30—filler fluid

32 a—bottom control electrodes

32 b—top control electrodes

FIG. 2 Pump assembly

FIG. 3 Drop meter

34—contact pad

36—cutoff electrode

FIG. 4 Active reservoir

38—hydrophobic rim

40—reservoir electrodes

FIG. 5 Array

42 a—transport lines

42 b—test areas

FIG. 6 Vortexer

44—sectorial electrode

FIG. 7 Zero-dead-volume valve

62—gate electrode

64 a—first supply line

64 b—second supply line

64 c—common line

FIG. 8 Decade dilutor

46—diluent line

48—reagent supply line

50—vortexer

52—undiluted reagent outlet

54—first stage outlet

56—second stage outlet

58—third stage outlet

60—fourth stage outlet

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, there is provided a chamber filled with afluid, with flat electrodes 32 a,b on opposite surfaces (FIG. 1). Thechamber is formed by the top 22 and the bottom 24 wafers. Themanipulated liquid is presented in the form of droplets 26. The fluid 30filling the chamber should be immiscible with the liquid that is to bemanipulated, and be less polar than that liquid. For example, if liquid26 is an aqueous solution, the filling fluid 30 may be air, benzene, ora silicone oil. The electrodes have electrical connections allowing anoutside control circuit to change their potentials individually or ingroups. At least some of the electrodes have insulating, hydrophobiccoating 28 a,b separating them from the inside of the chamber, and thevoltage is applied in such a manner that no DC voltage difference isapplied to any two non-insulated electrodes.

EXAMPLE 1 A Pump

The linear arrangement of electrodes shown in FIG. 2 is an integralpump. A droplet of polar liquid, or a streak of several electrodelengths, can be moved along by applying a wetting potential to anelectrode on one side of it and removing the wetting potential from thelast electrode under the other side of the streak.

To aid the effect of electrowetting in moving liquid from one electrodeto another, in a preferred embodiment the gap separating two adjacentelectrodes is not straight. Preferably, it has either sawtooth ormeander shape, preferably with rounded corners. The depths and widths ofthe interdigitated features of the adjacent electrodes are preferablychosen so as to promote moving liquid from one electrode to another whenthe voltage is applied to the latter electrode, as shown in FIG. 2 a-c.The initial position of the droplet 26 is shown in FIG. 2 a. Thehatching of an electrode 32 adjacent to the position of the dropletindicates that that electrode is connected to a voltage source. Thedroplet 26 moves (FIG. 2 b) so as to align itself with the electricfield of that electrode (FIG. 2 c).

EXAMPLE 2 A Drop Meter

As a convenient interface between a microfluidics device operating insubnanoliter to microliter range of volumes with the outside world, adrop meter is provided. The drop meter comprises an arrangement controlpads on one side of the chamber (FIG. 3 a). The contact pad 34 is eitherhydrophilic due to material it is made of, or due to a surfacetreatment, or made hydrophilic by applying a wetting potential to anunderlying electrode. The other two control pads have electrodes underthe hydrophobic surface.

To operate the drop meter, a wetting potential is first applied to thecutoff electrode 36 and the control electrode 32. As a result of this,the liquid which has covered the surface of the contact pad 34 spreadsover the other two pads, 32 and 36 (FIG. 3 b-d). Consequently, thewetting potential is removed from the cutoff electrode 36, making ithydrophobic again. Part of the liquid moves back to the contact pad 34,and is replaced on the cutoff electrode 36 with the filling fluid (FIG.3 e-f). As a result, an isolated droplet of liquid (26, FIG. 3 g) isformed on the control electrode 32. The size of the droplet isdetermined by the area of the control electrode 32 and the distancebetween the two surfaces forming the working chamber of the device.

EXAMPLE 3 An Active Reservoir

A reagent solution may be stored in an active reservoir in a sealeddevice and delivered under electronic control to a reaction site. Anexample of such reservoir is shown in FIG. 4. The delivery is effectedby applying the wetting potential to the first electrode 32 of thetransport line and removing the potential sequentially from thereservoir electrodes 40, for example beginning from the corner(s)furthermost from the transport line. To allow for long storage of thedevices with power off, the coating within the reservoir area is onlymoderately hydrophobic, and the rim 38 around that area is extremelyhydrophobic. The polar liquid will not spill beyond the rim 38, allowinglong shelf life of the device.

EXAMPLE 4 An Array

Droplets can be moved by electrowetting microactuators in more than onedirection. The array shown in FIG. 5 comprises test areas 42 b (hatched)and transport lines 42 a (open). Reagents are supplied through externaltransport lines, shown (broken) in the top part of the drawing. Wash andwaste lines are arranged similarly. The sources of the reagents may bereagent reservoirs as shown in FIG. 4, drop meters as in FIG. 3, orintegral dilution devices such as shown in FIGS. 6,8. In a preferredembodiment, the test pad electrodes are transparent, for example made ofindium tin oxide (ITO) or a thin, transparent metal film, to allow foroptical detection of molecules immobilized on the pad or trapped in thedroplet.

Such an array has utility as a system for parallel synthesis of manydifferent reagents. Both solid-phase synthesis of immobilized compoundsand liquid-phase synthesis using immobilized reagents, resins andcatalysts are possible. Another use of such an array is a fractioncollector for capillary electrophoresis or similar separation methods,whereby each fraction is isolated by a drop meter (similar to that shownin FIG. 3) and placed on its individual pad 32. This will allow longsignal accumulation time for optical and radioactive detection methodsand therefore improve sensitivity of analysis.

Important features of the electrodes in an array are the width of thegap between the electrodes and the shape of the electrode outline. Toavoid accidental mixing of droplets on the test pads, the gapsseparating those are straight and relatively wide. On the other hand,the electrodes in the transport lines preferably have interdigitatedsawtooth or meander outlines. The gaps between the test pad electrodesand transport line electrodes are also preferably of the meander orsawtooth types.

EXAMPLE 5 A Mixer/Vortexer

For controlled mixing of solutions, an integral mixer/vortexer isprovided (FIG. 6). It comprises a circular arrangement of sectorialelectrodes 44, some of which have transport line electrodes adjacent tothem. The necessary number of the sectors is filled with each solutionto be mixed by consecutively applying the wetting potential to therespective electrodes. The sectors initially filled with differentsolutions are preferably isolated from each other by the interspersedsectors with filler fluid. Then the potentials on the transport linesare removed, and those on sectorial electrodes are rearranged so as tobring the solutions into contact. The mixing action is achieved bysimultaneous removal of filler fluid from some of the sectors andfilling other sectors with the filler fluid. In particular, vortexeraction is achieved if this is done in a sequential fashion around thecircle.

Alternative configurations of electrodes are possible for achieving thesame goal of assisting in mixing solutions. For example, some of thesectors in an arrangement similar to that shown in FIG. 6 could be madenarrower and longer than the other sectors.

EXAMPLE 6 A Zero-Dead-Volume Valve

To rapidly exchange solutions contacting a particular pad in an array, azero-dead-volume valve is provided. An example of electrodeconfiguration for this application is shown in FIG. 8. Supply lines 64 aand 64 b are connected to the line 64 c through gate electrode 62.Either of the supply lines is operated in the manner described inExample 1, while wetting potential is applied to the gate electrode.Removal of the wetting potential from the gate electrode 62 allows tomove one of the solutions back up its supply line before the other istransported down its respective line. This arrangement has utility, forexample, in systems for determination of reaction kinetic constants.

EXAMPLE 7 A Decade Dilutor

A group of mixer/vortexers such as that shown in FIG. 6 can be used,complete with piping, for serial dilutions of reagents. An example of adecade dilutor with five decades is shown in FIG. 8. Each mixer in thedecade dilutor is operated in the manner described in the Example 5.Undiluted solution is passed directly through to the line 52; diluted 10times, down the line 54, and also to the next mixer 50; from there,solution diluted 100 times is passed both down the line 56 and to thenext mixer 50 and so forth.

Such dilutors have utility, for example, as elements of a system fordetermination of binding constants of labeled reagents in solution tothose immobilized on test pads of an array (similar to that shown inFIG. 5).

While the present invention has been described in terms of particularembodiments, it should be understood that the present invention lies inthe application of the electrowetting liquid propulsion principle toforming and manipulating discrete droplets of liquids rather than aparticular structure or configuration of the device. It will be obviousto those skilled in the art that a variety of electrode configurationsand arrangements can be substituted for those described in the Exampleswithout departing from the scope of the present invention. Inparticular, the dimensions in the figures should be understood only asillustrative examples rather than set dimensions defining the scope ofthe present invention.

1. A device comprising: (a) a first surface and a second surfaceseparated from one another to form a gap between the first and secondsurfaces; (b) a plurality of electrodes mounted on the first and secondsurfaces and facing the gap, wherein the plurality of electrodescomprises a single electrode on one of the surfaces; (c) an insulatorseparating at least a subset of the electrodes from the gap; and (d) adrop meter comprising a contact pad, a cutoff electrode, and a controlelectrode, wherein the contact pad is adjacent to the cutoff electrode,and the cutoff electrode is adjacent to the control electrode.
 2. Thedevice of claim 1 wherein the contact pad comprises an underlyingelectrode.
 3. The device of claim 1 wherein the contact pad comprises ahydrophilic surface.
 4. The device of claim 1 wherein the contact padhas a hydrophilic character imparted by a hydrophilic surface treatment.5. The device of claim 1 wherein the contact pad comprises a hydrophilicmaterial.
 6. The device of claim 1 wherein the plurality of electrodescomprises electrodes coupled by electrical connections to a controlcircuit.
 7. The device of claim 1 wherein the plurality of electrodescomprises electrodes comprising a hydrophilic surface.
 8. The device ofclaim 1 wherein the plurality of electrodes comprises a two-dimensionalarray of electrodes.
 9. The device of claim 1 wherein the plurality ofelectrodes comprises a linear arrangement of electrodes.
 10. The deviceof claim 1 wherein the plurality of electrodes comprises atwo-dimensional array of electrodes on one of the surfaces and theelectrodes on such surface are coated with an insulator.
 11. The deviceof claim 1 wherein the plurality of electrodes comprises an array ofelectrodes on the first surface and a single large electrode on thesecond surface.
 12. The device of claim 1 wherein the plurality ofelectrodes comprises substantially planar electrodes.
 13. The device ofclaim 1 wherein the plurality of electrodes comprises one or moresubstantially square electrodes.
 14. The device of claim 1 wherein theplurality of electrodes comprises a path or two-dimensional array of oneor more substantially square electrodes.
 15. The device of claim 1wherein the plurality of electrodes comprises one or more substantiallytriangular electrodes.
 16. The device of claim 1 wherein the gapcomprises a filler fluid therein.
 17. The device of claim 1 furthercomprising: (a) a filler fluid in the gap; and (b) a droplet in thefiller fluid.
 18. The device of claim 1 further comprising: (a) a fillerfluid in the gap; and (b) a polar droplet in the filler fluid.
 19. Thedevice of claim 1 wherein the gap comprises: (a) a filler fluid in thegap; and (b) a droplet in the filler fluid; wherein at least one ofthe-surfaces is preferentially wettable by the filler fluid relative tothe droplet.
 20. The device of claim 1 wherein the first and secondsurfaces are arranged to expose to the gap substantially parallel, flatsurfaces.
 21. The device of claim 1 comprising means for supplyingvoltage to the electrodes.
 22. The device of claim 1 comprising meansfor generating an electric potential to the electrodes.
 23. The deviceof claim 1 wherein the insulator is hydrophobic.
 24. The device of claim1, wherein the insulator comprises a hydrophobic coating.
 25. The deviceof claim 1 wherein: (a) the insulator comprises a hydrophobic surface;and (b) an electric field generated by one or more of the electrodessupplied with an electric potential causes a portion of the hydrophobicsurface to take on a hydrophilic character.
 26. The device of claim 1wherein: (a) the insulator comprises a hydrophobic surface; (b) the gapcomprises a filler fluid; (c) the filler fluid comprises an immiscibledroplet therein adjacent to an electrode; and (d) the immiscible droplethas a contact angle relative to the surface comprising the electrode,which contact angle is increased relative to the contact angle of theimmiscible droplet in the presence of an electric potential.
 27. Adevice comprising: (a) a first surface and a second surface separatedfrom one another to form a gap between the first and second surfaces,wherein the gap comprises a filler fluid; (b) a plurality of electrodesmounted on the first and second surfaces and facing the gap; (c) aninsulator separating at least a subset of the electrodes from the gap,wherein the insulator comprises a hydrophobic surface; and (d) a dropmeter comprising a contact pad, a cutoff electrode, and a controlelectrode, wherein the contact pad is adjacent to the cutoff electrode,and the cutoff electrode is adjacent to the control electrode; whereinthe filler fluid comprises an immiscible droplet therein adjacent to anelectrode, and the immiscible droplet has a contact angle relative tothe surface comprising the electrode, which contact angle is increasedrelative to the contact angle of the immiscible droplet in the presenceof an electric potential.
 28. The device of claim 27 wherein the contactpad comprises an underlying electrode.
 29. The device of claim 27wherein the contact pad comprises a hydrophilic surface.
 30. The deviceof claim 27 wherein the contact pad has a hydrophilic character impartedby a hydrophilic surface treatment.
 31. The device of claim 27 whereinthe contact pad comprises a hydrophilic material.
 32. The device ofclaim 27 wherein the plurality of electrodes comprises electrodescoupled by electrical connections to a control circuit.
 33. The deviceof claim 27 wherein the plurality of electrodes comprises electrodescomprising a hydrophilic surface.
 34. The device of claim 27 wherein theplurality of electrodes comprises a two-dimensional array of electrodes.35. The device of claim 27 wherein the plurality of electrodes comprisesa linear arrangement of electrodes.
 36. The device of claim 27 whereinthe plurality of electrodes comprises a two-dimensional array ofelectrodes on one of the surfaces and the electrodes on such surface arecoated with an insulator.
 37. The device of claim 27 wherein theplurality of electrodes comprises a single electrode on one of thesurfaces.
 38. The device of claim 27 wherein the plurality of electrodescomprises an array of electrodes on the first surface and a single largeelectrode on the second surface.
 39. The device of claim 27 wherein theplurality of electrodes comprises substantially planar electrodes. 40.The device of claim 27 wherein the plurality of electrodes comprises oneor more substantially square electrodes.
 41. The device of claim 27wherein the plurality of electrodes comprises a path or two-dimensionalarray of one or more substantially square electrodes.
 42. The device ofclaim 27 wherein the plurality of electrodes comprises one or moresubstantially triangular electrodes.
 43. The device of claim 27 whereinthe immiscible droplet comprises a polar droplet.
 44. The device ofclaim 27 wherein at least one of the-surfaces is preferentially wettableby the filler fluid relative to the droplet.
 45. The device of claim 27wherein the first and second surfaces are arranged to expose to the gapsubstantially parallel, flat surfaces.
 46. The device of claim 27comprising means for supplying voltage to the electrodes.
 47. The deviceof claim 27 comprising means for generating an electric potential to theelectrodes.
 48. The device of claim 27 wherein the insulator ishydrophobic.
 49. The device of claim 27 wherein the insulator comprisesa hydrophobic coating.
 50. The device of claim 27 wherein an electricfield generated by one or more of the electrodes supplied with anelectric potential causes a portion of the hydrophobic surface to takeon a hydrophilic character.